• NKG2D enhances cytotoxicity and survival of CD8 1 T cells, which contributes to GVHD and GVT effects after allogeneic HSCT.• The temporally distinct expression pattern of NKG2D ligands may allow separation of GVHD and GVT effects by transient NKG2D blockade.In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versushost disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8 1 T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8 1 T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCTrecipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8 1 T cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8 1 T cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8 1 T cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate